Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation. [Display omitted] •Combined inactivation of Ezh2 and Runx1 in ETPs induces their expansion in mice•Expanded ETPs show characteristic transcriptional features of ETP leukemia•Addition of Flt3-ITD generates an acute lympho-myeloid leukemia, propagated by ETPs•Both mouse and human ETP leukemias display sensitivity to BET inhibition Booth et al. show that inactivation of Ezh2 and Runx1 in early thymic progenitors (ETPs) causes cell expansion and gene expression changes similar to those seen in human ETP leukemia. Addition of Flt3-ITD to the Ezh2−/−;Runx1−/− ETP cells leads to aggressive leukemia, which is sensitive to BET inhibition.